Atherosclerosis is the major cause of death and disability in the United States and throughout the world. The lesions of atherosclerosis have a non-uniform distribution in the human vasculature. Straight regions of arteries are exposed to steady laminar blood flow (L-flow) and are protected from atherosclerosis, whereas regions of bifurcations and curvatures are characterized by disturbed blood flow (D-flow) that are predisposed to atherosclerosis. It is unrealistic to alter the architecture of the human vascular tree such as elimination of the arterial curvature or bifurcation; however, if we completely understand the signaling pathways conferring L-flow atheroprotection, we will be able to produce the atheroprotective action in D-flow areas of arteries by pharmacological or molecular means to prevent atherogenesis. Thus, our central goal is to identify the key signaling molecules in the anti-atherogenic programs of L-flow and to explore whether targeting these molecules could lead to atheroprotection in the D-flow regions of arteries. In our recent preliminary studies we have uncovered a unique epigenetic pathway that contributes to differential regulation of endothelial gene transcription programs in response to the atheroprotective laminar flow versus the atheroprone disturbed flow. In this proposal, we will explore the H3K27me3-dependent epigenetic mechanisms underlying L-flow versus D-flow effects on endothelial gene expression and atherosclerosis using the combinations of cell culture systems and animal models. Results from our proposed studies will reveal important and innovative molecular mechanisms underlying the hemodynamic forces-dependent atherogenesis, which may identify new therapeutic strategies for the treatment of atherosclerotic vascular diseases.